1. Field
The invention relates to regulation of cytokine production, particularly in vitro and in vivo enhancement of lymphokine production by T cell lymphocytes which are exposed to particular types of steroid hormones prior to cellular activation, and applications thereof.
2. State of the Art
It is known that lymphocytes exported from the thymus undergo a series of differentiation events which confer upon them the capacity to recognize and respond to specific peptide antigens presented appropriately in the context of self major histocompatibility complex (MHC) moelcules (Bevan, J. Exp. Med., 142:1349 (1975); Zinkernagel et al., J. Exp. Med., 141:1427 (1975)). Mechanistically, thymic maturation is a complex process which includes an irreversible rearrangement of T cell receptor genes (Hedrick et al. Nature, 308:149 (1984); Yanagi et al., Nature, 308:145 (1984)), the cell surface expression of these gene products as a disulfide-linked heterodimer (Meur et al., J. Exp. Med., 158:988 (1983); Kappler et al., Cell, 35:295 (1983)), positive and negative selection processes to provide appropriate restriction and avoidance of self reactivity (Von Boehmer et al., Immunol. Rev., 101:5 (1988)), and the synthesis and expression of CD4 or CD8 as accessory adhesion molecules (Bierer et al., Ann. Rev. Immunol., 7:579 (1989); Dembic et al., Nature, 320:232 (1986)). Microenvironmental influences within the thymus play an essential role in the fidelity of this process.
Subsequent to leaving the thymic microenvironment, mature T lymphocytes gain access to the recirculating T cell pool where they move freely via the blood between mucosal and nonmucosal lymphoid compartments in the mammalian host (Hamann et al., Immunol. Rev., 108:19 (1989)). T-lymphocyte expression of lymphoid tissue-specific homing receptors, which are complementary for vascular addressins on high endothelial venules present in Peyer's patches and peripheral lymph nodes, provide a biochemical means for selectivity to this recirculation process (Hamann et al., Immunol. Rev., 108:19 (1989)). Non-activated lymphocytes can move freely between mucosal and nonmucosal lymphoid tissues due to the presence of both types of homing receptors on their plasma membranes (Pals et al. Immunol., Rev., 108:111 (1989)). Effector lymphocytes, and antigen-activated immunoblasts which are stimulated in a particular site in the body, however, exhibit a far more selective migratory behavior. These cells move primarily to tissues originally involved in antigen exposure and cellular activation (Hamann et al., Immunol. Rev., 108:19 (1989); Pals et al., Immunol. Rev., 108:111 (1989)).
An immune response is initiated following T cell recognition of antigen peptides in the context of self MHC molecules and generally takes place in one of the host's secondary lymphoid compartments. Cellular activation is triggered by the binding of antigen to the T cell receptor (TCR), forming an antigen/TCR complex which transduces the antigen-specific extracellular stimulation across the plasma membrane, and generates intracellular signals which include the activation of protein kinase C and the increases in intracellular calcium (Alcover et al., Immunol. Rev., 95:5 (1987); Gelfand et al., Immunol. Rev., 95:59 (1987)). While signal transduction can lead to T cell unresponsiveness (Mueller et al., Ann. Rev. Immunol., 7:445 (1989)), positive signal transduction events trigger a series of additional biochemical processes. One consequence of this activation is the stimulated production of a number of biologically active molecules which are collectively termed lymphokines (Alcover et al., Immunol. Rev., 95:5 (1987); Gelfand et al., Immunol. Rev., 95:59 (1987)).
The lymphokines, many of which function primarily through autocrine and paracrine mechanisms, serve to mediate numerous effector functions controlled by T cells through their capacity to regulate cellular proliferation, differentiation and maturation events in lymphocytes, plus other hematopoietic and somatic tissue cells (Paul, Cell, 57:521 (1989)).
Each of the various types of lymphokines exhibit pleiotropic activities, dependent upon the specific type of cellular targets being stimulated. The biological evaluation of recombinant forms of specific lymphokines has determined that individual species can possess both distinct and overlapping cellular activities (Paul, Cell, 57:521 (1989); Mossman et al., Ann. Rev. Immunol., 7:145 (1989)). Interleukin-2 (IL-2) and interleukin-4 (IL-4), for example, share the capacity to facilitate T cell growth but are disparate in their relative contribution to cellular and humoral immune responses. Cloned T cell lines, restricted in their capacity to produce individual species of lymphokines, have been described which demonstrate unique capabilities in serving as effector cells or helper cells for various types of immune responses (Paul, Cell, 57:521 (1989); Mossman et al., Ann. Rev. Immunol., 7:145 (1989); Hayakawa et al., J. Exp Med., 168:1825 (1988)).
Immunosuppression in animals can result from a depressed capacity to produce species of lymphokines which are essential to the development of protective forms of immunity. Imbalances between various types of lymphokines, where species of lymphokines capable of promoting one form of immune response exhibit enhanced production, while those lymphokines needed to promote protective forms of immunity are suppressed, can also lead to immunosuppression. It is known that animals may be immunosuppressed as a consequence of endogenous elevations in adrenal glucocorticosteroid (GCS) levels. This condition could result from vital infections, certain bacterial infections, certain parasitic infections, cancer, some autoimmune syndromes, stress, trauma, post-surgical trauma, burn trauma or as a secondary consequence to any clinical condition which causes an elevated production of interleukin-1 (IL-1). Plasma GCS levels can also be elevated exogenously as a consequence of therapeutic treatment for a variety of clinical conditions. It is also well known that certain essential functions of the immune system decline with age, a situation which correlates with elevations in adrenal output of GCS and depressions in production of other types of adrenal steroid hormones.
Known pharmaceutical products and theraputic methods for treating immunosuppressed animals having depressions or imbalances in their ability to produce interleukins have focused on the production and purification of IL-2 by activated T cells, or the production of IL-2 through genetic engineering techniques, followed by the therapeutic administration of this IL-2 or IL-2 administration with a muramyldipeptide in an attempt to restore normal propagation of T cells. Illustrative of such prior art are the disclosures of U.S. Pat. No. 4,661,447 issued Apr. 28, 1987 to Fabricius et al., U.S. Pat. No. 4,780,313 issued Oct. 25, 1988 to Koichiro et al. and U.S. Pat. No. 4,789,658 issued Dec. 6, 1988 to Yoshimoto et al. The side effects of therapeutic approaches of the prior art of systemic administration of recombinant IL-2 are numerous. Such side effects include fever, hypotension, hepatic and renal failure, myocardial infarctions, capillary leak syndrome, and massive edema (Dinatello et al., New England J. of Med., 317:940 (1987)).
Also disclosed in the prior art is the theraputic use of the adrenal androgen steroid dehydroepiandrosterone (DHEA) to treat maladies such as diabetes, dry skin, occular hypertension, obesity, and retroviral infections. Illustrative of such prior art teachings are the disclosures of U.S. Pat. No. 4,395,408 issued Jul. 26, 1983 to Torelli et al., U.S. Pat. No. 4,518,595 issued May 21, 1985 to Coleman et al., U.S. Pat. No. 4,542,129 issued Sep. 17, 1985 to Orentreich, U.S. Pat. No. 4,617,299 issued Oct. 14, 1986 to Knepper, U.S. Pat. No. 4,628,052 issued Dec. 9, 1986 to Peat, U.S. Pat. No. 4,666,898 issued May 19, 1987 to Coleman et al., European Patent Application No. 0 133 995 A2 dated Feb. 8, 1984 (inventor: Schwartz et al.), and UK Patent Application No. GB 2 204 237 A dated Apr. 14, 1988 (inventor: Prendergast).